The compounds of Formula I are described as 11,12-secoprostaglandins because of their structural relationship to the naturally-occurring prostaglandins.
The prostaglandins constitute a biologically prominent class of naturally-occurring, highly-functionalized C.sub.20 fatty acids which are anabolized readily in a diverse array of mammalian tissues from three essential fatty acids; namely, 8,11,14-eicosatrienoic acid, 5,8,11,14-eicosatetraenoic acid, and 5,8,11,14,17-eicosapentaenoic acid. Each known prostaglandin is a formal derivative of the parent compound, termed "prostanoic acid"; the latter is a C.sub.20 fatty acid covalently bridged between carbons 8 and 12 such as to form a trans, vicinally-substituted cyclopentane in which the carboxy-bearing side chain is "alpha" or below the plane of the ring, and the other side chain is "beta" or above the plane of the ring as depicted in formula III: ##STR3##
Prostaglandins have been shown to occur extensively in low concentrations in a myriad of mammalian tissues where they are both rapidly anabolized and catabolized and to exhibit a vast spectrum of pharmacological activities including prominent roles in (a) functional hyperemia, (b) the inflammatory response, (c) the central nervous system, (d) transport of water and electrolytes, and (e) regulation of cyclic AMP. Further details concerning the prostaglandins can be found in recent reviews of their chemistry [J. E. Pike, Fortschr. Chem. Org. Naturst., 28, 313 (1970) and G. F. Bundy, A. Rep. in Med. Chem., 7, 157 (1972)]; biochemistry [J. W. Hinman, A. Rev. Biochem., 41, 161 (1972)]; pharmacology [J. R. Weeks, A. Rev. Pharm., 12, 317 (1972)]; physiological significance [E. W. Horton, Physiol. Rev., 49, 122 (1969)]; and general clinical application [J. W. Hinman, Postgrad. Med. J., 46, 562 (1970)].
The potential application of natural prostaglandins as medicinally useful therapeutic agents in various mammalian disease states is obvious but suffers from three formidable major disadvantages, namely, (a) prostaglandins are known to be rapidly metabolized in vivo in various mammalian tissues to a variety of metabolites which are devoid of the desired original biological activities, (b) the natural prostaglandins are inherently devoid of biological specificity which is requisite for a successful drug, and (c) although limited quantities of prostaglandins are presently produced by both chemical and biochemical processes, their production cost is extremely high; and consequently, their availability is quite restricted.
Our interest has, therefore, been to synthesize novel compounds structurally related to the natural prostaglandins, but with the following unique advantages: (a) simplicity of synthesis leading to low cost of production; (b) specificity of biological activity which may be either of a prostaglandin-mimicking or prostaglandin-antagonizing type; (c) enhanced metabolic stability. The combination of these advantages serves to provide effective, orally and parenterally active therapeutic agents for the treatment of a variety of human and animal diseases. Included are applications in renal, cardiovascular, gastrointestinal, respiratory, and reproductive systems, and in the control of lipid metabolism, inflammation, blood clotting, skin diseases, growth hormone release, selected cancers, and certain autoimmune diseases.
The compounds of the present invention are useful as pharmaceutically active compounds. Thus, these compounds are orally active in the treatment of conditions which are responsive to the actions of the natural prostaglandins. It is, of course, necessary to determine by routine laboratory testing which of the compounds of the present invention are most suitable for a specific end use. Some of the compounds of the invention have prostaglandin-like activity in that they mimic the effect of prostaglandin E.sub.1 in stimulating the formulation of cyclic AMP in the mouse ovary in vitro.
Examples of compounds which are useful in stimulating the formation of cyclic AMP in the mouse ovary are:
(a) 8-acetyl-12-hydroxyheptadecanoic acid PA1 (b) 8-acetyl-13-hydroxyheptadecanoic acid PA1 (c) 8-acetyl-14-hydroxyheptadecanoic acid PA1 (d) 8-acetyl-11-hydroxyheptadecanoic acid PA1 (e) 8-acetyl-12-hydroxy-(E)-10-heptadecenoic acid PA1 (f) 8-propionyl-12-hydroxyheptadecanoic acid PA1 (g) 8-(3-hydroxypropionyl)-12-hydroxyheptadecanoic acid PA1 (h) 8-(1-hydroxyethyl)-12-hydroxyheptadecanoic acid PA1 (i) 8-hydroxymethyl-12-hydroxyheptadecanoic acid PA1 (j) 8-acetyl-12-hydroxy-16-methylheptadecanoic acid PA1 (k) 8-acetyl-12-hydroxynonadecanoic acid PA1 (l) 8-(1,3-dihydroxypropyl)-12-hydroxyheptadecanoic acid PA1 (m) 9-acetyl-12-hydroxyheptadecanoic acid PA1 (n) 8-acetyl-12-acetoxyheptadecanoic acid PA1 (o) (5-acetyl-9-hydroxytetradecyloxy)acetic acid PA1 (p) methyl 8-acetyl-12-hydroxyheptadecanoate PA1 (q) 8-glycoloyl-12-hydroxyheptadecanoic acid PA1 (r) 8-acetyl-12-hydroxy-13,13-dimethylheptadecanoic acid PA1 (s) 8-acetyl-12-hydroxy-10-heptadecynoic acid PA1 (t) 8-(1-hydroxy-1-methylethyl)-12-hydroxy-12-methylheptadecanoic acid PA1 (u) 8-acetyl-11-(1-hydroxycyclohexyl)-10-undecynoic acid PA1 (v) 8-(1-hydroxyethyl)-12-hydroxy-(E)-10-heptadecenoic acid PA1 (w) 8-(1-hydroxyethyl)-12-hydroxy-12-methylheptadecanoic acid PA1 (a) 8-acetyl-12-hydroxyheptadecanoic acid PA1 (b) 8-acetyl-13-hydroxyheptadecanoic acid PA1 (c) 8-acetyl-14-hydroxyheptadecanoic acid PA1 (d) 8-acetyl-11-hydroxyheptadecanoic acid PA1 (e) 8-acetyl-12-hydroxy-(E)-10-heptadecenoic acid PA1 (f) 8-propionyl-12-hydroxyheptadecanoic acid PA1 (g) 8-(1-hydroxyethyl)-12-hydroxyheptadecanoic acid PA1 (h) 8-hydroxymethyl-12-hydroxyheptadecanoic acid PA1 (i) 8-acetyl-12-hydroxynonadecanoic acid PA1 (j) 8-acetyl-12-acetoxyheptadecanoic acid PA1 (k) (5-acetyl-9-hydroxytetradecyloxy)acetic acid PA1 (l) 8-acetyl-12-hydroxy-13,13-dimethylheptadecanoic acid PA1 (m) 8-acetyl-11-(1-hydroxycyclohexyl)undecanoic acid PA1 (a) 8-acetyl-12-hydroxyheptadecanoic acid PA1 (b) 8-(1-hydroxyethyl)-12-hydroxyheptadecanoic acid PA1 (c) (5-acetyl-9-hydroxytetradecyloxy)acetic acid
Certain of the compounds of the invention which do not mimic the effect of prostaglandin E.sub.1 are active as antagonists of prostaglandin E.sub.1 in certain smooth muscle tissues, such as intestinal and uterine tissue. Such components would be useful in the prevention of abortion and in the treatment of diarrhea.
An example of the compounds of our invention active in antagonizing the effect of prostaglandin E.sub.1 in uterus and intestinal tissue are compounds which have additional methyl substituents in the alpha position relative to the carboxy group, as for example, 2-methyl-8-acetyl-12-hydroxyheptadecanoic acid.
In addition, certain of the compounds of the present invention mimic the effects of prostaglandin E.sub.1 in producing renal vasodilation in laboratory animals. Thus, they can be used to improve renal function in animals with poorly-functioning kidneys. Examples of such compounds are:
Also, certain of the compounds of this invention have antihypertensive activity as shown by the fact that they lower blood pressure in a strain of laboratory rats which have blood pressure higher than that observed in normal rats, and thus are useful in the treatment of hypertension. An example of such a compound is 8-acetyl-12-hydroxyheptadecanoic acid.
In addition, certain of the compounds of this invention are effective in inhibiting the aggregation of platelets in blood stimulated with collagen to cause platelet aggregation. Thus, in inhibiting platelet aggregation, they are useful in preventing thrombus formation. Examples of compounds of this type are:
Also, certain of the compounds of our invention, for example 8-acetyl-12-hydroxyheptadecanoic acid, may have utility as antiulcer agents in that they are active in inhibiting gastric secretion in laboratory animals. In one test used to establish this activity, dogs with a chronic gastric fistula are treated with pentagastrin, a substance which ordinarily evokes secretion in such animals. Activity in the test compound is shown when the secretion caused by the test compound is inhibited to some degree.
The compounds of this invention are also indicated to be useful in therapy as regulators of the immune response. The basis for their activity in this area is their ability to stimulate cyclic-AMP formation in cells. Agents, including the E prostaglandins, that increase cellular cyclic-AMP concentration, interfere with the cell-mediated immune response by inhibiting lymphocyte expression in response to antigen, by inhibiting release of pathological mediators from sensitized lymphocytes, and by inhibiting the killing of target cells by such lymphocytes. Various assays which depend upon the measurement of some function of the immunologically competent lymphocyte can be used to demonstrate that the prostaglandin analogs of this invention are similarly active. For example, the release of lymphokines (proteins that are agents of inflammation and tissue destruction) from sensitized lymphocytes in culture is strongly inhibited by these analogs in low concentrations. Thus, it is apparent that the compounds of this invention are applicable to the treatment of those autoimmune diseases in whose pathogenesis a cell-mediated immune reaction is involved. Such diseases range from contact dermatitis to such chronic destructive diseases as rheumatoid arthritis and possibly multiple sclerosis and systemic lupus erythematosus.
The present prostaglandin analogs are also effective in preventing the rejection of transplanted organs. The biochemical basis for this action is the same as outlined in the preceding paragraph, for the rejection of organ grafts is considered to be predominantly a cell-mediated immune phenomenon and the hallmark of organ rejection is the infiltration of cytotoxic lymphocytes into the graft. Direct evidence that the compounds of this invention can retard or prevent transplant rejection has been obtained in the rat renal allograft model; in this system, administration of the compounds of the present invention prevents the rejection of the transplanted kidney and the subsequent death of the host rat, which events invariably occur in the cases of untreated rats or those treated with immunosuppressants. An example of a compound which is an effective regulator of immune responses of the types described above is 8-acetyl-12-hydroxyheptadecanoic acid.
Because of their biological activity and ready accessibility, the compounds of the invention are also useful in that they permit large scale animal testing useful and necessary to understanding of these various disease conditions such as dwarfism caused by poorly-functioning pituitary glands, stroke (thrombus formation), and the like. It will be appreciated that not all of the compounds of this invention have these biological activities to the same degree but the choice of any particular ones for any given purpose will depend upon several factors including the disease state to be treated.
The compounds of this invention can be administered either topically or systemically, i.e., intravenously, subcutaneously, intramuscularly, orally, rectally, or by aerosolization in the form of sterile implants for long action. They can be formulated in any of a number of pharmaceutical compositions and non-toxic carriers to this end.
The pharmaceutical compositions can be sterile, injectable suspensions or solutions, or solid orally-administrable, pharmaceutically-acceptable tablets or capsules; the compositions can also be intended for sublingual administration, or for suppository use. It is especially advantageous to formulate compositions in dosage unit forms for ease and economy of administration and uniformity of dosage. "Dosage unit form" as a term used herein refers to physically discrete units suitable as unitary dosages for animal and human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired biological effect in association with the required pharmaceutical means.
Illustratively, a sterile injectable composition can be in the form of aqueous or oleagenous suspensions or solutions.
The sterile injectable composition can be aqueous or oleagenous suspension or solution. Suspensions can be formulated according to the known art using suitable dispersing and wetting agents and suspending agents. Solutions are similarly prepared from the salt form of the compound. For the laboratory animals, we prefer to use incomplete Freund's adjuvant or sterile saline (9%) as carrier. For human parenteral use, such as intramuscularly, intravenously, or by regional perfusion, the diluent can be a sterile aqueous vehicle containing a preservative; for example, methylparaben, propylparaben, phenol, and chlorobutanol. The aqueous vehicle can also contain sodium chloride, preferably in an amount to be isotonic; as well as a suspending agent, for example, gum arabic, polyvinyl pyrrolidone, methyl cellulose, acetylated monoglyceride (available commercially as Myvacet from Distillation Products Industry, a division of Eastman Kodak Company), monomethyl glyceride, dimethyl glyceride or a moderately high molecular weight polysorbitan (commercially available under the tradenames Tween or Span from Atlas Powder Company, Wilmington, Delaware). Other materials employed in the preparation of chemotherapeutic compositions containing the compound may include glutathione, 1,2-propanediol, glycerol and glucose. Additionally, the pH of the composition is adjusted by use of an aqueous solution such as tris(hydroxymethyl)aminomethane (tris buffer).
Oily pharmaceutical carriers can also be used, since they dissolve the compound and permit high doses. Many oily carriers are commonly employed in pharmaceutical use, such as, for example, mineral oil, lard, cottonseed oil, peanut oil, sesame oil, or the like.
It is preferred to prepare the compositions, whether aqueous or oils, in a concentration in the range of from 2-50 mg./ml. Lower concentrations require needless qualities of liquid. Higher concentrations than 50 mg./mg. are difficult to maintain and are preferably avoided.
Oral administration forms of the drug can also be prepared for laboratory animals or human patients provided that they are encapsulated for delivery in the gut. The drug is subject to enzymatic breakdown in the acid environment of the stomach. The same dosage levels can be used as for injectable forms; however, even higher levels can be used to compensate for biodegradation in the transport. Generally, a solid unit dosage form can be prepared containing from 0.5 mg. to 25 mg. active ingredient.
Whatever the mode of administration, doses in the range of about 0.10 to 20 milligrams per kilogram of body weight administered one to four times per day are used. The exact dose depending on the age, weight and condition of the patient, and the frequency and route of administration.
The low cost and ready accessibility of the compounds of this invention make them particularly promising for applications in veterinary medicine in which field their utilities are comparable to those in human medicine.
In preparing the new chemical compounds with which this invention is concerned, we have found it desirable to use as starting materials compounds which are readily available commercially in any desired amounts.
There are a number of inter-related processes useful in preparing the compounds of Formula I. These can all be described as the sub-synthesis of each of the three main moieties of the molecule (i.e., the (CH.sub.2).sub.4 A-R chain, the ##STR4## chain; and the R' group; all attached to the asymmetric carbon atom ##STR5## and then their reaction(s) to form the desired end product. Although not all compounds can be prepared by each process, there is much overlapping so that many compounds can be prepared by one, two, or three of these processes. Certain variant processes are involved and each variant of the main processes will be discussed in relation to the specific compound or compounds produced.